Estimates of the location of L-type Ca2+ channels in motoneurons of different sizes: a computational study.

Canadian Institute for Health Research Group in Sensory-Motor Systems, Department of Physiology, Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.

Abstract

In the presence of monoamines, L-type Ca(2+) channels on the dendrites of motoneurons contribute to persistent inward currents (PICs) that can amplify synaptic inputs two- to sixfold. However, the exact location of the L-type Ca(2+) channels is controversial, and the importance of the location as a means of regulating the input-output properties of motoneurons is unknown. In this study, we used a computational strategy developed previously to estimate the dendritic location of the L-type Ca(2+) channels and test the hypothesis that the location of L-type Ca(2+) channels varies as a function of motoneuron size. Compartmental models were constructed based on dendritic trees of five motoneurons that ranged in size from small to large. These models were constrained by known differences in PIC activation reported for low- and high-conductance motoneurons and the relationship between somatic PIC threshold and the presence or absence of tonic excitatory or inhibitory synaptic activity. Our simulations suggest that L-type Ca(2+) channels are concentrated in hotspots whose distance from the soma increases with the size of the dendritic tree. Moving the hotspots away from these sites (e.g., using the hotspot locations from large motoneurons on intermediate-sized motoneurons) fails to replicate the shifts in PIC threshold that occur experimentally during tonic excitatory or inhibitory synaptic activity. In models equipped with a size-dependent distribution of L-type Ca(2+) channels, the amplification of synaptic current by PICs depends on motoneuron size and the location of the synaptic input on the dendritic tree.

Relationship between somatic voltage and current in response to current ramps (5 nA/s) for the small-, intermediate-, and large-sized motoneurons shown in during the resting (R), excitatory (E), and inhibitory (I) synaptic states. Arrows indicate somatic threshold for persistent inward current (PIC) activation. PIC threshold was measured as membrane potential at which derivative of somatic membrane potential with respect to time was 0.1 V/s. Tops of plateaus truncated to highlight differences in onset of PICs.

Location of the intersection points in a small (DVS 25–2) and large (DVS 14–1) motoneuron when somata are voltage clamped according to average PIC threshold values reported by . A: example of membrane potential profiles in a single dendritic path during the resting (R; solid lines) and excitatory (E; dashed lines) synaptic states. Black lines are based on average values reported by , and gray lines are based on somatic thresholds reported for low- and high-conductance motoneurons by and used in . Arrows indicate location of intersection points. B: comparison of distribution of intersection points for all dendritic paths for small and large motoneurons for conditions described in A. Black circles are based on average values reported by , and gray circles are based on somatic thresholds reported for low- and high-conductance motoneurons by . C: relationship between somatic voltage and current in responses to current ramps (5 nA/s) for small and large motoneurons when L-type Ca2+ channel hotspots are incorporated into models based on average PIC threshold values reported by . Arrows indicate somatic threshold for PIC activation. PIC threshold was measured as membrane potential at which derivative of somatic membrane potential with respect to time was 0.1 V/s.

Comparison of shift in somatic threshold of PIC activation from the resting to excitatory synaptic state and from the resting to inhibitory synaptic state. Open circle with cross-hairs indicates mean values and SD reported by . Closed circles indicate values for the 5 motoneurons used in this study when L-type Ca2+ channel hotspots are located at intersection points. Triangle and square indicate values for small (DVS 25–2) and large motoneurons (DVS 14–1), respectively, when L-type Ca2+ channel hotspots are located at same distance from soma as those in an intermediate-sized motoneuron (DVS 25–3).

Current reaching soma caused by activation of PICs and excitatory synaptic activity. Somatic membrane potential was clamped at − 64 mV. Excitation levels were varied by activating 4, 8, 16, 32, 64, and 100% of maximum number of excitatory synapses. These excitation levels were converted to an absolute number of synapses to examine somatic current for a given amount of synaptic input. A: passive condition. Models do not contain voltage-dependent channels on dendritic tree. B: active condition. Models contain L-type Ca2+ channel hotspots on dendrites and are positioned according to . Total current reaching soma is comprised of both passive and active currents. C: current reaching soma from PICs. This was determined by taking difference between total and passive currents in A and B. D: amplification of synaptic of current caused by PIC activation as a function of excitation level. Gray dashed line at 1.0 indicates no amplification. Closed circles, DVS 25–2, small motoneuron; open circles, DVS 25–3, intermediate-sized motoneuron; triangles, DVS 14–1, large motoneuron.

Total current reaching soma and amplification of synaptic current caused by activation of PICs when excitatory synaptic inputs are restricted to proximal (A and B), middle (C and D), and distal (E and F) one third of dendritic tree. Closed circles, DVS 25–2, small motoneuron; open circles, DVS 25–3, intermediate-sized motoneuron; triangles, DVS 14–1, large motoneuron. Gray dashed line at 1.0 indicates no amplification.